New Insights into 3D Gene Regulation Dynamics

Controlling which genes are active and which proteins are being produced at any given time through gene regulation is crucial for the correct functioning of cells.  Mis-regulation can lead to serious conditions, including developmental disorders and diseases like cancer, as cells may grow uncontrollably or fail to respond properly to signals. Effective gene regulation allows organisms to manage growth, repair, and immune responses efficiently. Within this context, a better understanding of how this complex regulation works is vital, and the focus of a PRX Life article published at the end of August 2024. 

Our study is the first in which someone explored the idea that insulators may be interacting weakly with surrounding chromatin rather than with themselves

This study, led by Umeå University researchers Lucas Hedström and Ludvig Lizana in collaboration with Ralf Metzler at the University of Potsdam, offers a fresh perspective on how cells control gene expression using spatially separated enhancers and insulators. Enhancers are short DNA sequences that amplify gene activity by binding with proteins to promoter sites, while insulators act as physical barriers blocking enhancers from doing just that. Traditional models suggested that insulators interact directly with each other to reduce enhancer-promoter contacts. However, the study authors now challenge that view by introducing a stochastic model where insulators bind weakly to the surrounding DNA instead of each other. 

To put it in simpler terms, says Ludvig Lizana, Associate professor at the Department of Physics and IceLab, you could imagine two pieces of tape. “The tape doesn’t need to stick to another tape – tape can stick weakly to other surfaces too. With insulators, we think that they don’t have to attach to each other – connecting to the chromatin, the DNA strand, is enough to block an enhancer from amplifying the expression of a gene as long as its physically blocking it.” 

Illustration of DNA in which an orange insulator sequence creates a physical block by binding to the DNA strand, preventing a green enhancer sequence from binding to a blue promoter sequence to amplify gene expression.

Lucas Hedström, doctoral student at the Department of Physics and study author, explains how they came to propose this model: “Yuri Schwartz’s group recently presented new experimental data, published in Science Advances in February 2023, that challenged the current paradigm in insulator function. With this in mind, we built a new model to show that perhaps not all cell regulation is equal, but rather that there might be more mechanisms at play.” 

By simulating these regulatory interactions, the researchers found good agreement with experimental three-dimensional DNA contact interaction data (Hi-C) from the screen of hundreds of insulator elements in Drosophila from Yuri Schwartz’s study. The researchers also found significant variability in how long it takes enhancers to connect with target genes, indicating that gene regulation operates on a more unpredictable timescale than previously thought. This variability may have important implications for understanding gene expression dynamics in complex organisms. 
 
Study author Ludvig Lizana expands on this point: “Our study is the first in which someone explored the idea that insulators may be interacting weakly with surrounding chromatin rather than with themselves. Our work offers new insights into the relationship between local three-dimensional genome folding and gene activation, which could reshape how we approach gene regulation research. These findings might also lead to breakthroughs in how we understand the regulation of developmental gene clusters that require precise control over gene expression and, potentially, gene therapy and synthetic biology.”